CABA - Cabaletta Bio: Expanding The Success Of CAR-T Beyond Oncology

2023-12-11 05:58:05 ET

Summary

• Cabaletta Bio is developing targeted cellular therapies for autoimmune diseases, including systemic lupus erythematous and myositis.
• Their lead program, CABA-201, is a CD19 chimeric antigen receptor (CAR) T cell therapy currently in phase 1/2 clinical trials.
• Academic studies have shown the efficacy of CD19 CAR T cell therapy in treating autoimmune diseases, supporting Cabaletta's approach.

Cabaletta Bio ( CABA ) develops potentially curative targeted cellular therapies for a host of autoimmune diseases. It is among a host of companies using CART therapies for potentially treating diseases beyond oncology. Cabaletta is a spinout from UPenn, having been founded by Penn’s Aimee Payne, M.D., Ph.D., and Michael Milone, M.D., Ph.D., a co-inventor of Novartis’ CAR-T cancer therapy Kymriah. The company is in IND stages, and has no trial data. Lead program is CABA-201, a fully human CD19 chimeric antigen receptor ((CAR)) T cell therapy containing a 4-1BB co-stimulatory domain. CABA-201 is being developed for targeting systemic lupus erythematous, myositis, systemic sclerosis and generalized myasthenia gravis, and is currently running phase 1/2 clinical trials.

The 4-1BB (CD137) co-stimulatory domain is one of the several co-stimulatory domains that can be incorporated into the CAR construct. It is derived from a cell surface protein called 4-1BB, which is a member of the tumor necrosis factor receptor superfamily. When this co-stimulatory domain is included in the CAR design, it serves to enhance the activation and persistence of the engineered T cells.

The incorporation of co-stimulatory domains like 4-1BB is aimed at improving the overall effectiveness and durability of CAR-T cell therapy. Although CABA-201 does not have any clinical trial data yet, trials performed in the academic domain with a CD19 CART construct containing a 4-1BB co-stimulatory domain exactly like CABA-201 does have results.

One of these trials , whose data was published in Nature Medicine last year, used anti CD19 CART in 5 patients with SLE under a compassionate use program. Professor Georg Schett, whose group at Friedrich Alexander University Erlangen-Nuremberg published this leading study, is now a member of Cabaletta’s scientific advisory board.

Here’s the data, rephrased from the original:

The median age was 22 years (range: 6), with a median disease duration of 4 years (range: 8). Despite active disease (median SLE Disease Activity Index: 16, range: 8) refractory to multiple immunosuppressive treatments, these patients received autologous T cells transduced with a lentiviral anti-CD19 CAR vector.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients were reinfused with CAR T cells at a dose of 1 × 10^6 CAR T cells per kg body weight. In vivo expansion of CAR T cells resulted in profound B cell depletion, clinical symptom improvement, and normalization of laboratory parameters, including seroconversion of anti-double-stranded DNA antibodies.

After three months, all five patients achieved remission of SLE based on DORIS criteria, with a median SLE Disease Activity Index score of 0 (range: 2). Drug-free remission persisted during a longer follow-up period (median: 8 months, range: 12 months post-CAR T cell administration), even after the reappearance of B cells, which occurred approximately 110 ± 32 days after CAR T cell treatment. The reappearing B cells were characterized as naïve with non-class-switched B cell receptors.

The CAR T cell treatment demonstrated good tolerance, with only mild cytokine-release syndrome observed. These findings suggest that CD19 CAR T cell transfer is not only feasible and well-tolerated but also highly effective in treating SLE.

Commenting on the logic of using antiCD19 CART against autoimmune diseases originating at B cells, Professor Schett wrote in a letter to the editors of NEJM:

Systemic lupus erythematosus ((SLE)) is a severe autoimmune disease that predominantly affects young women. SLE is characterized by the formation of autoantibodies and immune complex–mediated inflammation and organ damage. Although autoreactive B cells play a key role in the pathogenesis of SLE, B-cell depletion by antibodies has only limited therapeutic efficacy. This paradox has been attributed to the inaccessibility and persistence of autoreactive B cells within lymphatic organs and inflamed tissues or the pathologic role of CD20-negative plasma cells, which may act as an additional source of autoantibodies in patients with SLE. Chimeric antigen receptor ((CAR))–modified T cells that have been genetically engineered to recognize CD19 and other B-cell surface antigens have emerged as a powerful tool for the treatment of relapsed or refractory B-cell cancers. This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE.

Another study, published in Lancet, reported the case of “a patient with an idiopathic inflammatory myopathy who was successfully treated with CD19 CAR T cells.” This patient was refractory to intravenous rituximab, which, after initial success, failed to control the disease in a follow up infusion. A second transient improvement was observed with intravenous immunoglobulins followed by oral tacrolimus, but this too faded quickly.

Following this lack of remission and considerable painful symptoms, anti CD19 CART treatment was initiated after tapering of previous treatments at the time of leukapheresis (13 days before CAR T-cell administration). The patient had a spurious worsening of conditions possibly due to cytokine release syndrome, however he quickly regained full muscle strength and showed strong and sustained improvement in various other symptoms, an effect thus far unachievable with prior treatments.

The authors conclude:

Taken together, this case shows the feasibility, tolerability, and efficacy of CAR T-cell therapy for the treatment of idiopathic inflammatory myopathies. We observed a complete resolution of antisynthetase syndrome in this patient despite the cessation of all immunosuppressive drugs, and this resolution was sustained even after the reconstitution of B cells. Although short-term effects cannot be completely ruled out, the fast and complete recovery of all haematopoietic lineages within 1 week, the lack of response to previous cyclophosphamide treatment, and the deep and sustained response even after B-cell recovery suggest that conditioning therapy might not have substantially contributed to the treatment response.

A third case study treating severe SSc with CD19-targeting CAR-T-cells, “that are used to deeply deplete B-cells in refractory lymphoma and leukemia, showed remarkable effects in refractory systemic lupus erythematosus patients, suggesting the principle feasibility to intercept with autoimmune disease via CD19-targeting CAR-T-cells.”

The authors conclude:

We show for the first time that CAR-T-cell therapy can result in the fast loss of SSc-specific autoimmunity in a patient with severe, diffuse SSc and is paralleled by amelioration of clinical manifestations including skin- and heart-fibrosis and arthritis. Further studies with longer follow-up times and more patients will help to further characterize the role of CAR-T-cell therapy in SSc.

This is the academic background behind CABA-201, which, like we mentioned earlier, is very similar to the CART constructs used in these studies. It is currently running Phase 1/2 myositis, SLE, generalized myasthenia gravis & systemic sclerosis trials. These studies, incorporating independent, parallel 6 patient cohorts, have initial doses identical to the academic studies. Initial data is expected in 1H2024.

Financials

CABA has a market cap of $695mn and a cash balance of $164mn. Research and development expenses were $13.8 million for the three months ended September 30, 2023, while general and administrative expenses were $4.9 million. At that rate, the company has a cash runway of 7-8 quarters, even considering the increasing trial expenses as things move forward. After its INDs cleared in May, CABA was able to raise $85mn from a secondary offering, demonstrating the market enthusiasm for its programs.

CABA is largely owned by institutions, followed by hedge funds. Fred Alger Management, Adage and Cormorant are the key holders.

Bottomline

CABA is a pioneer in using CART for autoimmune diseases. Its strategy is based on successful work done in academia, and looks promising. There is considerable market enthusiasm, as evinced by the successful fundraising. I would like to watch this one for its upcoming data, and may take a pilot position at some point before or after.

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